Enantioselective organocatalytic hydride reduction

Article abstract of DOI:10.1021/ja043834g

The first enantioselective organocatalytic hydride reduction has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of β,β-substituted αβ-unsaturated aldehydes to generate β-stereogenic aldehydes. The use of imidazolidinone 2 as the asymmetric catalyst has been found to mediate the transfer of hydrogen to a large class of enal substrates from ethyl Hantzsch ester. The capacity of catalyst 2 to accelerate E-Z isomerization prior to selective E-olefin reduction allows the implementation of geometrically impure enals in this operationally simple protocol. Copyright

Full text of DOI:10.1021/ja043834g

Published on Web 12/09/2004
Enantioselective Organocatalytic Hydride Reduction
Ste´phane G. Ouellet, Jamison B. Tuttle, and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received October 10, 2004; E-mail: Dmacmill@caltech.edu
Table 1. Effect of Catalyst and Solvent on EOHRa
Within the vast architectural subclass known as stereogenicity,
hydrogen is found to be the most common substituent. Not surpris-
ingly, therefore, the field of enantioselective catalysis has focused
great attention on the invention of hydrogenation technologies over
the last 50 years.1 While these powerful transformations rely mainly
entry
catalyst
HX
solvent
time (h)
% conversionb
% eec
on the use of organometallic catalysts and hydrogen gas, it is
intriguing to consider that the large majority of hydrogen bearing
stereocenters are created in biological cascade sequences involving
enzymes and hydride-reduction cofactors such as NADH or
FADH2.2 On this basis, we recently questioned whether the concep-
tual blueprints of biochemical hydride addition might be employed
in a chemical reduction wherein enzymes and cofactors are replaced
by small molecule organocatalysts and dihydropyridine analogues.
In this context, we report the development of the first enantio-
selective organocatalytic hydride reduction (EOHR),3 a bio-inspired
protocol that formally allows the enantioselective transfer of hydro-
gen from Hantzsch esters to enal-olefins using amine catalysts.4
1
2
3
4
5
6
7
8
L-proline
TFA
TFA
TFA
HCl
toluene
toluene
toluene
toluene
toluene
CHCl3
CHCl3
CHCl3
5
1
1
8
31
1
47
96
95
70
19
99
90d
91d
15
75
88
81
87
85
93
93
1
2
1
2
2
2
2
HCl
TFA
TFA
TCA
24
23
a R ) CO2Et. b Conversion determined by GLC analysis. c Enantiomeric
excess determined by chiral GLC analysis (Bodman Γ-TA). d At -30 °C.
Table 2. Effect of Dihydropyridine Component on EOHRa
entry
hydrogen source
time (h)
% conversionb
% eec
1
2
3
4
5
6
7
NADH
N-Bn-nicotanamide
R ) CO2Et
24
26
7
-
15
92
94
57
54
45
-
88
92
88
89
80
86
R ) CO2Bn
R ) CO2Me
R ) COPh
7
26
24
26
R ) COMe
a Experiment as shown in eq 1 at -30 °C. b Conversion by GLC analysis.
c Enantiomeric excess by chiral GLC analysis (Bodman Γ-TA).
revealed in Table 1, exposure of 3-methyl-(E)-cinnamaldehyde to
ethyl Hantzsch ester8 in the presence of L-proline resulted in
inefficient and nonselective reduction (entry 1). In contrast, a
dramatic increase in enantioselectivity and reaction efficiency was
achieved using our imidazolidinone catalysts 1 and 2 (entries 2-8,
g75% ee). A survey of reaction media for this organocatalytic
hydride delivery revealed that CHCl3 provides the highest levels
of enantiocontrol at subambient temperatures (entry 7, 93% ee).
The superior levels of asymmetric induction and efficiency exhibited
by amine salts 2‚TFA or 2‚TCA in CHCl3 at -30 °C to afford
(S)-3-phenylbutanal in g92% ee prompted us to select these
conditions for further exploration.
Our laboratory has reported that the LUMO-lowering activation
of R,â-unsaturated aldehydes via the reversible formation of
iminium ions is a useful platform for the development of enantio-
selective cycloadditions5a and π-nucleophile alkylations.5b On this
basis, we began to consider that the enantioselective reduction of
R,â-unsaturated aldehydes6 might be accomplished using dihydro-
pyridine analogues7 in the presence of iminium catalysts. As
The utility of various dihydropyridine reagents has been inves-
tigated (Table 2, eq 1). To our surprise, NADH was not a viable
reagent, whereas N-benzylnicotinamide was quite selective (entry
2, 88% ee). While a range of reduced pyridines that incorporate
electron withdrawing groups is useful, the ethyl Hantzsch ester
proved to be superior (entry 3, 93% ee).
9
32
J. AM. CHEM. SOC. 2005, 127, 32-33
10.1021/ja043834g CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Effect of Aldehyde Substituents on EOHR
We next examined the influence of the aldehyde olefin geometry
on the sense of asymmetric induction. As shown in eqs 2 and 3,
we were surprised to find that isomerically pure E- and Z-olefin
substrates conVerge to the same (S)-enantiomer. As such, imple-
mentation of the corresponding E:Z olefin mixture provides
excellent levels of enantiocontrol (eq 4, 90% ee). This result stands
in marked contrast to most metal-mediated hydrogenations wherein
olefin geometry dictates enantiospecific reductions.9 Preliminary
studies have shown that the origin of stereoconvergence in our case
arises from catalyst accelerated E-Z isomerization prior to selective
hydride delivery to the E-olefin isomer. We anticipate that the
capacity to tolerate starting materials of low geometric purity will
greatly enhance the general utility of this operationally simple
asymmetric reduction.
Experiments that probe the scope of the R,â-unsaturated aldehyde
component are summarized in Table 3. Given the capacity of
catalyst 2 to rapidly isomerize disubstituted enals, we were surprised
to find that this asymmetric hydride reduction can accommodate
â,â-olefin substituents of similar steric demand (entries 1-6, R1
) Me, Et; R2 ) Ar, c-hex). For example, high levels of
enantiocontrol are obtained with the ethyl-cyclohexyl combination
(entry 6, 95% yield, 91% ee), a transformation that can differentiate
the geometric location of methine and methylene substituents in a
dynamic kinetic resolution. Moreover, the presence of a silyloxy
group allows selective partitioning of a similar methylene-methyl
relationship (entry 8, 74% yield, 90% ee). Variation in the electronic
nature of the aldehyde component has little influence on the inherent
enantiocontrol. Indeed, good levels of asymmetric induction are
available with enals that do not readily participate in iminium
formation (entry 7, R1 ) CO2Me, 83% yield, 91% ee), as well as
aldehydes that provide stable iminium intermediates (entry 2, R1
) Ph, 91% yield, 93% ee). The severe steric constraints of the
tert-butyl adduct are rapidly overcome at 23 °C (entry 9, 97% ee,
95% yield, 5 min). Importantly, this mild hydride-delivery method
is compatible with functional groups that are often susceptible to
reduction (e.g., aldehydes and halogens, entry 4, 92% yield, 97%
ee).
a Enantiomeric excess determined by chiral GLC analysis. b Performed
at -45 °C. c Using 10 mol % catalyst. d Yield determined by NMR. e Using
5 mol % catalyst at 23 °C. f Performed at -50 °C.
References
(1) (a) Akabori, S.; Sakurai, S.; Izumi, Y.; Fujii, Y. Nature 1956, 178, 323.
(b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (c)
Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008.
(2) Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J. D.
Molecular Biology of the Cell, 3rd ed.; Garland: New York & London,
2002.
(3) This complete study was first presented orally at the Lilly Grantee
Symposium, Indianapolis, IN, March 1, 2003.
(4) The conjugate reduction of Wieland-Miescher ketone has previously been
accomplished with Hantzsch ester: (a) Pandit, U. K.; Mas Cabre´, F. R.;
Gase, R. A.; de Nie-Sarink, M. J. J. Chem. Soc., Chem. Commun. 1974,
627. (b) de Nie-Sarink, M. J.; Pandit, U. K. Tetrahedron Lett. 1979, 26,
2449
(5) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Austin, J. F.; MacMillan, D. W. C. J Am. Chem.
Soc. 2002, 124, 1172.
(6) Keinan, E.; Greenspoon, N. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, Chapter
3.5, p 523.
In summary, we have developed the first organocatalytic hydride
reduction, an operationally simple reaction that allows the enantio-
and chemoselective transfer of hydrogen from Hantzsch esters to
geometrically impure enals. Full details of this survey along with
catalytic procedures for cyclic and acyclic enone reduction will be
described shortly.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen, Lilly,
and Merck. S.G.O. is grateful for an NSERC fellowship.
(7) (a) Stout, D. M.; Meyers, A. I. Chem. ReV. 1982, 82, 223. (b) Lavilla, R.
J. Chem. Soc., Perkin Trans. 1 2002, 1141.
(8) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(9) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Lipshutz, B. H.;
Servesko, J. M. Angew. Chem., Int. Ed. 2003, 41, 4789.
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA043834G
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 33